The Food and Drug Administration has approved gefitinib (Iressa) for the initial treatment of metastatic epidermal growth factor receptor–positive (EGFR-positive) non–small-cell lung cancer (NSCLC) that carries exon 19 deletions or exon 21 substitution mutations.
Labeling expansion of a companion diagnostic test, therascreen EGFR RGQ PCR Kit, also was approved.
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“The approval of Iressa provides physicians and patients in the U.S. with a new choice of first-line treatment for metastatic non–small cell lung cancer,” Antoine Yver, head of oncology, global medicines development at AstraZeneca, said in a statement released July 13.
The oral EGFR tyrosine kinase inhibitor was approved based on the results of the single-arm, open-label, phase IV study [IFUM (Iressa Follow-Up Measure)] reporting a 50% response rate by independent review and 6-month median duration of response to once-daily gefitinib 250 mg in 106 treatment-naive patients with metastatic EGFR-positive NSCLC.
The efficacy results were supported by an exploratory analysis in a subset of patients with EGFR-positive metastatic adenocarcinoma NSCLC receiving first-line treatment in the pivotal IPASS (Iressa Pan-ASia Study). Among these 186 patients, the objective response rate (ORR) by independent review was 67% with a median duration of response of 9.6 months for gefitinib vs. an ORR of 41% and 5.5-month duration of response for carboplatin and paclitaxel (Abraxane). Median progression-free survival was 10.9 months and 7.4 months, respectively, according to the FDA statement.
Gefitinib gained initial approval in 2003 under the FDA’s accelerated approval process based on positive results in a randomized phase II trial in patients with advanced NSCLC failing two prior lines of chemotherapy. Gefitinib was withdrawn from the market in 2005, however, amid calls from the public, after failing to improve mortality in several trials including a phase III trial in patients failing first or second-line therapy.
In August 2014, gefitinib was granted orphan drug designation for the treatment of EGFR mutation-positive NSCLC.
For the current approval, the safety of gefitinib was evaluated in 1,129 patients in a double-blind randomized trial. The most common all-grade adverse events in order of decreasing frequency were skin reactions, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, proteinuria, and diarrhea. The most common grade 3/4 adverse events were proteinuria, diarrhea, increased ALT, decreased appetite, increased AST, and skin reactions. About 5% of patients discontinued gefitinib because of an adverse event.
Serious and uncommon adverse drug reactions were also evaluated in 2,462 patients with NSCLC who received gefitinib monotherapy in three randomized trials. Significant adverse reactions were interstitial lung disease (1.3%), fatal hepatotoxicity (0.04%), and grade 3 ocular disorders (0.1%), according to the FDA.
The recommended dose of gefitinib is 250 mg once daily until disease progression or unacceptable toxicity. Full prescribing information is available here.